1. Field of the Invention
This invention relates generally to drug compositions. More particularly, this invention relates to antidiabetic drug compositions which may be taken orally.
2. Description of the Prior Art
The human as well as other animal organisms need insulin, the pancreas hormone, in order to utilize the glucoses. Insulin stimulates the movement of the glucose from the blood into the tissue cells, especially the muscular cells, and expedites the synthesis of fats as well as of proteins in practically all organs. In diabetics, the pancreas will not produce this hormone in sufficient quantities, with the result that the glucose level in the blood rises, causing the known symptoms of diabetes mellitus. Thus,it becomes necessary to supply the diabetic with the required amount of this hormone by parenteral, that is subcutaneous, injections of insulin of other origin in order to maintain the sugar content of the blood at a normal or at least permissible level. Such injections require strict control and individual treatment of the respective patient.
Specific sulfonyl ureas which may be administered orally, are known to possess a blood sugar reducing effect because of their ability to stimulate insufficient insulin secretion in adult diabetics, and especially in those cases were diabetes occurs during old age. In this connection, see "Arzneimittel," Volume 1, Pharmakodynamica, Verlag Chemie 1968, pp. 896 to 908. However, sulfonyl ureas may have side effects, such as gastro-intestinal disturbances, toxic depressions of the bone marrow, widespread exanthemata and the like, depending on the dosage. In this connection, see Mehnert et al, "Diabetologie in Klinik und Praxis," [G. Thieme, Stuttgart (1974) ], pp. 18 to 23. In such instances it is necessary to reduce the dosage, possibly resulting in a rise of the blood sugar level above that which is permissible.
It is also known that an enzyme called "kallikrein" (German) is also produced by the pancreas and has a proteolytic effect. In this connection, see Frey et al, "Klinische Wochenschrift" (1932), pp. 846 to 849. In addition to its vasodilatoric and blood-pressure reducing effects, this enzyme also has the ability to lower slightly the blood sugar, and it is stated that this effect will occur even if the enzyme is applied orally. In this study it was also found that after administering the substance for several days, for example after three days, the effect would diminish or disappear. Thus, there was detected a tachyphylaxy, delimiting the therapeutic usefulness of this substance. The blood-sugar-reducing effect has not been confirmed by any other source. In this connection, see Elmer et al, "Klinische Wochenschrift," (1932), pp. 1993 to 1995.
For these reasons neither the kallikrein nor the so-called kinins (which are liberated by the enzyme action of the kallikrein from certain albuminous substances, the kininogenes, and which have the pharmacological activity of the kallikreins) have been utilized as anti-diabetic drugs. These kinins are oligopeptides having 9 to 11 amino acid units. The nonapeptide Brady kinin with the amino acid sequence (NH.sub.2) arginine -- proline- proline -glycine - phenylalanine - serine - proline - phenylalanine - arginine (COOH) and the decapeptide kallidin, extended by a lysine residue which is added to the amino end, as well as the meth-lys-Brady kinin, which is lengthened still further by the addition of a methionine residue, are substances which, when applied even in minimum quantities, have a kallikrein-like vasodilatoric effect on the circulation, will cause the relaxed muscular system to contract and will also cause vehement local pain reactions if injected subcutaneously even at minimum quantities. In this connection, see Werle, "Angewandte Chemie," (1961), pp. 689 to 720; "Arzneimittel," Volume 1, Verlag Chemie (1968), pp. 876 to 880.
It is also known from the published German patent application 2 357 507 that the kinins, such as Brady kinin and kallidin, promote the mobility of the spermatozoa, and they are therefore recommended as means to enhance fertility, for example, in artificial insemination.
The search has continued for improved anti-diabetic drug compositions which may be administered orally. This invention was made as a result of that search.